Simple motor reflexes are wired into the brain at a very basic level, yet the strength and quickness of these reflexes are modified by environmental stimuli that occur just before the elicitation of the reflex. Such motor reflex modulation depends on processing of sensory information, attention and motivation. In vertebrates, a well-characterized motor reflex modulated by environmental stimuli is the startle response, a fast, whole body reaction to sudden sensory stimuli. The display of a sub-threshold stimulus just prior to a startling stimulus, suppresses the startle response. This phenomenon of prepulse inhibition (PPI) has been described in pigeons, mice and humans. In humans, PPI is impaired in several cognitive disorders, including schizophrenia, and returns after administration of antipsychotic drugs. Despite its clinical importance, however, the molecular and cellular pathways underlying PPI are not very well understood. We have recently discovered that zebrafish larvae exhibit prepulse inhibition, and that this inhibition is modulated by some of the same pharmacological agents known to modulate PPI in mammals. Furthermore, we have devised an experimental setup that allows us to screen with high throughput for mutants with defects in startle response modulation, including PPI. The objective of this proposal is to generate a large mutant collection, thereby forming a platform for integrative studies aimed to understand the neural, molecular and clinical aspects of reflex regulation, such as PPI. The experiments in this proposal will: (1) screen an equivalent of 1,500 mutagenized genomes for defects in the startle response regulation such as PPI and sub-threshold sensitivity (through automated high-speed video analysis);(2) define the defects in the isolated mutants (a) by testing their sensitivity to neurotransmitter agonists and antagonists known to modulate PPI;b) by testing their performance in an additional startle modulation paradigm, habituation;and (3) map and clone selected mutants (through a combined candidate/positional cloning approach). These studies are directly relevant to the study of human diseases, as defects in PPI have been described in several disorders, including schizophrenia, attention deficit disorder, obsessive-compulsive disorder, Huntington's disease and Tourette's syndrome. Moreover, PPI is also affected in tobacco and MDMA ('ecstasy') users, and in children with a parental history of alcoholism.